Combinations of a 4-pyrimidinesulfamide derivative with active ingredients for the treatment of endothelin related diseases

ABSTRACT

The present invention concerns the compound aprocitentan, {5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide, and its use as endothelin receptor antagonist, in combination with other active ingredients or therapeutic agents including an angiotenin receptor blocker, and/or a calcium channel blocker, and preferably a diuretic which is a thiazide-like diuretic, in the prophylaxis or treatment of certain endothelin related diseases. The invention further relates to pharmaceutical compositions comprising aprocitentan in combination with said other active ingredients or therapeutic agents. The invention further relates to such pharmaceutical compositions comprising novel crystalline forms of aprocitentan.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a Continuation of U.S. application Ser. No.16/489,227, filed on Aug. 27, 2019, now issued as U.S. Pat. No.11,174,247, which claims benefit under 35 U.S.C. 371 to PCT ApplicationNo. PCT/EP2017/078371, filed on Nov. 6, 2017, which claims the benefitof PCT Application Nos. PCT/EP2017/054489, filed on Feb. 27, 2017, andPCT/EP2017/061487, filed on May 12, 2017, the contents of each of whichare incorporated herein by reference.

The present invention concerns the compound aprocitentan and its use asendothelin receptor antagonist, in combination with other activeingredients or therapeutic agents including an angiotenin receptorblocker (especially valsartan), and/or a calcium channel blocker(especially amlodipine), and preferably a diuretic which is athiazide-like diuretic (especially hydrochlorothiazide orchlorthalidone), in the prophylaxis or treatment of certain endothelinrelated diseases. The invention further relates to pharmaceuticalcompositions comprising aprocitentan in combination with said otheractive ingredients or therapeutic agents. The invention further relatesto such pharmaceutical compositions comprising novel crystalline formsof aprocitentan; pharmaceutical compositions prepared from suchcrystalline forms, and to the use of such crystalline forms incombination with said other active ingredients or therapeutic agents inthe prophylaxis or treatment of said endothelin related diseases.

Aprocitentan,{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamide(hereinafter also referred to as “COMPOUND”), has the formula I

The compound of formula I, also known under the name, and referred to asACT-132577, is an endothelin receptor inhibitor and useful as endothelinreceptor antagonist. The compound of formula I is a member of astructural family that was previously generically disclosed in WO02/053557. In particular, the compound of formula I, while showingendothelin receptor antagonist activity, exhibits in vivo a much longerhalf-life and a much shorter clearance in comparison to correspondingalkylated derivatives. This makes the compound of formula I particularlysuitable for long-acting pharmaceutical compositions, as disclosed in WO2009/024906.

Because of its ability to inhibit the endothelin binding, the compoundof formula I can be used for treatment of endothelin related diseaseswhich are associated with an increase in vasoconstriction, proliferationor inflammation due to endothelin. Examples of such diseases arehypertension, pulmonary hypertension, coronary diseases, cardiacinsufficiency, renal and myocardial ischemia, renal failure, cerebralischemia, dementia, migraine, subarachnoidal hemorrhage, Raynaud'ssyndrome, digital ulcers and portal hypertension. They can also be usedin the treatment or prevention of atherosclerosis, restenosis afterballoon or stent angioplasty, inflammation, stomach and duodenal ulcer,cancer, melanoma, prostate cancer, prostatic hypertrophy, erectiledysfunction, hearing loss, amaurosis, chronic bronchitis, asthma,pulmonary fibrosis, gram negative septicemia, shock, sickle cell anemia,glomerulonephritis, renal colic, glaucoma, connective tissue diseases,therapy and prophylaxis of diabetic complications, complications ofvascular or cardiac surgery or after organ transplantation,complications of cyclosporin treatment, pain, hyperlipidemia as well asother diseases, presently known to be related to endothelin. Particularexamples of endothelin related diseases are hypertension relateddiseases comprising hypertension including especially difficult totreat/resistant hypertension; pulmonary hypertension; heart failureincluding especially chronic heart failure; reducing the risk ofdeveloping a major cardiovascular event (such as heart failure,myocardial infarction, stroke, or death from cardiovascular causes) inpatients who are at cardiovascular risk (such as patients who havecoronary artery disease and/or patients who have demonstrated clinicalsigns of congestive heart failure); angina pectoris; and diastolicdysfunction; erectile dysfunction; CKD (especially CKD of stages 1 to 4as defined by the Kidney Disease Improving Global Outcomes (KDIGO)Guidelines (and notably CKD of stage 3), and in particular CKD of thesestages caused by/associated with essential hypertension, especiallyresistant hypertension); and diabetes, and diabetes related diseasessuch as diabetic arteriopathy, diabetic nephropathy, diabeticretinopathy, diabetic vasculopathy; and reducing the risk of developinga major cardiovascular event (such as heart failure, myocardialinfarction, stroke, or death from cardiovascular causes) in patients whohave diabetes that is accompanied by at least one other cardiovascularrisk factor (such as hypertension, especially resistant hypertension).

According to the 2014 American Society of Hypertension and InternationalSociety of Hypertension joint statement [Weber et al., “ClinicalPractice Guidelines for the Management of Hypertension in the Community.A Statement by the American Society of Hypertension and theInternational Society of Hypertension.” J Clin Hypertens (2014), 16(1),14-26], the 2013 European Society of Hypertension and European Societyof Cardiology joint guideline [Mancia et al, J. Hypertens. (2013), 31,1281-1357], as well as several national guidelines [Denolle et al., JHum Hypertens. (2016), 30(11), 657-663; McCormack et al., Br J Cardiol(2013), 20 (suppl 1), S1-S16], resistant hypertension (rHT) (ordifficult to treat hypertension) is defined as uncontrolled bloodpressure (BP) (i.e., failure to lower BP to a pre-defined threshold)despite concurrent administration of three antihypertensive therapies ofdifferent pharmacological classes at maximal or optimal doses, includinga diuretic. Thus, resistant hypertension patients include patients whoseblood pressure is controlled with use of more than three medications.That is, patients whose blood pressure is controlled but require four ormore medications to do so should be considered resistant to treatment(see e.g. Mancia et al, J. Hypertens. (2013)).

Clinical studies have shown that endothelin receptor antagonists (ERAs)may have significant treatment effect in patients suffering fromhypertension and/or renal disease. However, therapeutic benefit needs tobe weighted against potential side effects, such as the potential riskof teratogenic activity. In addition, both, selective ET_(A)-antagonistsand dual antagonists of both the ET_(A) and ET_(B) receptor, may causefluid retention, a common side effect associated with many previouslystudied ERAs. Whereas the risk-benefit balance is in most cases in favorof treatment with an ERA for indications such as pulmonary hypertension(as reflected in the past by successive market approvals e.g. for theERAs the dual antagonists bosentan and macitentan, the ET_(A)-selectiveantagonist ambrisentan), ERAs have no role in the management of primaryhypertension (Laffin et al. Seminars in Nephrology 2015, 35, 168-175),and side effects such as fluid retention may remain an issue when apotential treatment of rHT, chronic kidney disease or other hypertensionrelated diseases with an ERA is considered.

The ET_(A)-selective endothelin receptor antagonist darusentan has beenin development for the treatment of rHT (Bakris et al., Hypertension2010, 56, 824-830, see also WO2007/098390). In a 14 week phase 3 trialin patients with rHT, it demonstrated efficacy on the reduction ofambulatory blood pressure, but failed to show significant treatmenteffect on the primary endpoint systolic blood pressure. Patients wereeligible to participate if they had treatment resistant hypertension(systolic blood pressure of higher than 140 mm Hg) despite treatmentwith three or more antihypertensive drugs from different drug classes,including a diuretic, at optimized doses. A minimum dose of 25 mg perday of hydrochlorothiazide (or its equivalent for other thiazidediuretic drugs) was required. Even though during the trial diuretictherapy could be intensified at the discretion of the investigators tomanage fluid retention, the most frequent adverse event associated withdarusentan was fluid retention/edema at 28% versus 12% in each of theother groups. More patients withdrew because of adverse events ondarusentan as compared with placebo.

WO2016/073846 provides a comprehensive summary of ERAs tested forvarious indications including CKD and rHT. Similarly to the observationsmade for darusentan mentioned above, also the ET_(A)-selective ERAavosentan, in a trial that investigated the use of avosentan to reduceproteinuria in patients with diabetes, showed significant treatmenteffect, associated with a significantly increased discontinuation oftrial medications due to adverse events, predominantly related to fluidoverload and congestive heart failure. The trial was terminatedprematurely, and the authors conclude that “it may be that at dosages of25 to 50 mg, avosentan is less selective for the ETA receptor and thuscaused sodium and water retention and peripheral vasodilation with apotential fluid shift from the intravascular to extravascular space. Theassumption of ETB receptor blockade with higher dosages of avosentan isfurther supported by data that showed a natriuretic effect of selectiveETA receptor blockade in people who were treated with ACEIs (Mann etal., J Am Soc Nephrol. 2010, 21(3): 527-535.” WO2016/073846 providesfurther examples where fluid retention may have led to increased sideeffects for the ERAs bosentan, tezosentan, ambrisentan, and atrasentan.WO2016/073846 concludes in proposing a method of treating CKD with anERA, especially with the ET_(A)-selective ERA atrasentan, usingpredictors of fluid retention; said method comprising the determinationof a risk of fluid retention if an ERA were administered to the subject;and administering the ERA to the subject if the risk is at an acceptablelevel.

Preclinical and clinical data suggest that the ET_(A)-selectiveantagonists sitaxentan and ambrisentan pose a greater risk of fluidretention than the dual ERAs bosentan and macitentan (Vercauteren etal., JPET 2017, 361, 322-333). On the other hand, pre-clinical datashowed that the synergistic effect on blood pressure of anET_(A)-selective ERA in combination with the ACE inhibitor enalapril wasabolished by simultaneous blockade of the ET_(B)-receptor (Goddard etal., J. Am. Soc. Nephrol. 2004, 15, 2601-2610).

It has been shown in a phase 2 trial that aprocitentan, an ERA resultingin effective dual blockade of the endothelin receptors, may result inefficacious control of blood pressure in subjects having essentialhypertension, i.e. without background therapy (Actelion PharmaceuticalsLtd, press release May 22, 2017). The overall frequency of adverseevents was similar to those observed in the placebo group. Thus,different from the methods of WO2016/073846 no risk assessment and/ordose reduction to mitigate side effects related to fluid retention maybe required for aprocitentan when used in the treatment of hypertensionrelated diseases, especially resistant hypertension.

Moreover, it has been found in rat models of hypertension thataprocitentan may have synergistic pharmacological effect in combinationwith valsartan, and synergistic pharmacological effect in combinationwith amlodipine, compared to the effect of the respective activeingredients alone. In particular, when combined with threeantihypertensive therapies of different pharmacological classesincluding valsartan, amlodipine, and a diuretic of the thiazide classsuch as commercially available Exforge HCT® (i.e. a fixed dosecombination of valsartan/amlodipine/hydrochlorothiazide), aprocitentanmay result in superior effect than spironolactone which is a standardavailable add-on treatment. Moreover, aprocitentan may have a differentpharmacological profile than the predominantly ET_(A)-selectiveantagonists so far tested in resistant hypertension and otherendothelin-related diseases. Thus, aprocitentan, an ERA resulting ineffective dual blockade of the endothelin receptors, may be particularlysuited for the treatment of resistant hypertension when prescribed incombination with one or more antihypertensive therapies of differentpharmacological classes, including especially an angiotensin receptorblocker such as especially valsartan, a calcium channel blocker such asespecially amlodipine, and a diuretic, especially a diuretic of thethiazide class (a thiazide-like diuretic) such as especiallychlorothiazide, chlorthalidone, hydrochlorothiazide, indapamide, ormetolazone. Such combination treatment may result in superior control ofblood pressure compared to the treatment with such antihypertensivetherapies alone, while maintaining a benign side effect profile even atoptimal efficacious dosages of aprocitentan, not requiring e.g. the riskassessment methods of WO2016/073846 and/or dose reductions to mitigateside effects, e.g. related to fluid retention.

It has further been found that certain crystalline forms of aprocitentanthat are suitable for the production of pharmaceutical compositions mayunder certain conditions be found. Said crystalline forms of COMPOUNDare novel and may have advantageous properties in view of the potentialuse of COMPOUND as active pharmaceutical ingredient. Such advantages mayinclude better flow properties; less hygroscopicity; betterreproducibiliy in manufacturing (for example better filtrationparameters, better reproducibility of formation, and/or bettersedimentation); and/or defined morphology. Such crystalline forms ofCOMPOUND may be particularly suitable in a process of manufacturingcertain pharmaceutical compositions. It has also been found thatCOMPOUND or a pharmaceutically acceptable salt thereof is particularlyuseful to treat certain disorders, in particular when used incombination with other active ingredients or therepeutic agents.

DESCRIPTION OF THE FIGURES

FIG. 1 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form A as obtained from Example 1. The X-ray diffractiondiagram shows peaks having a relative intensity, as compared to the mostintense peak in the diagram, of the following percentages (relative peakintensities given in parenthesis) at the indicated angles of refraction2theta (selected peaks from the range 3-33° 2theta with relativeintensity larger then 10% are reported): 9.8° (18%), 9.9° (18%), 11.7°(14%), 14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%),17.8° (100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%), 21.9°(10%), 22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%), 25.1° (20%),25.3° (24%), 25.6° (33%), 25.9° (16%), 27.1° (23%), 27.3° (39%), 28.5°(13%), 29.0° (23%), 29.4° (15%), 30.1° (12%) and 30.6° (10%).

FIG. 2 shows the X-ray powder diffraction diagram of a dichloromethanesolvate of the COMPOUND in a crystalline form B as obtained from Example2. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensities given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 11.2° (16%), 16.2° (57%), 18.0° (21%), 18.6° (71%), 18.8°(36%), 19.8° (19%), 20.3° (100%), 22.4° (45%), 22.9° (28%), 24.3° (44%),24.8° (11%), 25.0° (41%), 25.7° (22%), 26.1° (31%), 27.4° (20%), 29.4°(16%), 29.8° (38%) and 32.4° (12%).

FIG. 3 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form C as obtained from Example 3. The X-ray diffractiondiagram shows peaks having a relative intensity, as compared to the mostintense peak in the diagram, of the following percentages (relative peakintensities given in parenthesis) at the indicated angles of refraction2theta (selected peaks from the range 3-33° 2theta with relativeintensity larger then 10% are reported): 7.8° (23%), 9.7° (42%), 15.7°(37%), 17.2° (16%), 17.8° (15%), 18.8° (26%), 19.8° (71%), 20.1° (51%),20.6° (15%), 21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6° (40%), 24.1°(23%), 24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%), 26.8° (19%),27.1° (16%), 28.5° (31%), 30.8° (13%) and 30.8° (13%).

FIG. 4 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form D as obtained from Example 4. The X-ray diffractiondiagram shows peaks having a relative intensity, as compared to the mostintense peak in the diagram, of the following percentages (relative peakintensities given in parenthesis) at the indicated angles of refraction2theta (selected peaks from the range 3-33° 2theta with relativeintensity larger then 10% are reported): 4.6° (27%), 8.4° (15%), 8.6°(11%), 16.4° (17%), 16.8° (26%), 17.2° (10%), 18.6° (11%), 18.9° (18%),19.3° (40%), 19.6° (45%), 20.1° (100%), 20.6° (55%), 20.8° (26%), 22.0°(10%), 22.7° (14%), 23.0° (24%), 23.5° (32%), 23.8° (12%), 24.2° (17%),24.7° (20%), 25.1° (55%), 25.4° (22%), 25.6° (14%), 26.2° (16%), 26.8°(17%), 27.2° (28%), 28.1° (21%) and 28.1° (19%).

FIG. 5 shows the X-ray powder diffraction diagram of an acetonitrilesolvate of the COMPOUND in a crystalline form E as obtained from Example5. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensities given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 9.0° (21%), 9.5° (56%), 11.3° (61%), 14.5° (41%), 14.8°(15%), 15.6° (47%), 16.0° (26%), 16.5° (100%), 18.2° (84%), 18.7° (73%),18.9° (56%), 20.2° (20%), 20.7° (56%), 22.8° (96%), 23.9° (22%), 24.5°(70%), 25.3° (77%), 25.6° (29%), 26.0° (14%), 26.6° (66%), 27.5° (27%),29.6° (31%), 30.2° (66%) and 33.0° (13%).

FIG. 6 shows the X-ray powder diffraction diagram of COMPOUND in acrystalline form J as obtained from Example 6. The X-ray diffractiondiagram shows peaks having a relative intensity, as compared to the mostintense peak in the diagram, of the following percentages (relative peakintensities given in parenthesis) at the indicated angles of refraction2theta (selected peaks from the range 3-33° 2theta with relativeintensity larger then 10% are reported): 4.0° (44%), 4.7° (14%), 6.5°(23%), 9.0° (27%), 16.1° (40%), 17.2° (11%), 18.7° (22%), 19.0° (58%),19.4° (28%), 19.8° (46%), 20.7° (57%), 21.2° (17%), 21.9° (100%), 22.6°(14%), 23.2° (23%), 24.1° (37%), 24.8° (40%), 25.6° (42%), 27.0° (29%),28.2° (27%), 29.0° (20%), 30.3° and 30.8° (10%).

FIG. 7 shows the X-ray powder diffraction diagram of a dimethylsulfoxidesolvate of the COMPOUND in a crystalline form K as obtained from Example7. The X-ray diffraction diagram shows peaks having a relativeintensity, as compared to the most intense peak in the diagram, of thefollowing percentages (relative peak intensities given in parenthesis)at the indicated angles of refraction 2theta (selected peaks from therange 3-33° 2theta with relative intensity larger then 10% arereported): 10.9° (16%), 16.9° (18%), 18.2° (26%), 18.4° (30%), 18.6°(29%), 18.7° (55%), 19.3° (100%), 20.8° (35%), 21.2° (47%), 21.9° (26%),24.3° (21%), 24.8° (24%), 25.4° (29%), 25.8° (22%), 26.7° (34%), 27.7°(13%), 27.8° (14%), 28.6° (15%), 29.4° (18%), 31.5° (23%) and 31.8°(12%).

FIG. 8 shows the X-ray powder diffraction diagram of an ethanol solvateof the COMPOUND in a crystalline form L as obtained from Example 8. TheX-ray diffraction diagram shows peaks having a relative intensity, ascompared to the most intense peak in the diagram, of the followingpercentages (relative peak intensities given in parenthesis) at theindicated angles of refraction 2theta (selected peaks from the range3-33° 2theta with relative intensity larger then 10% are reported): 9.1°(31%), 9.3° (34%), 11.3° (49%), 12.2° (10%), 14.6° (17%), 14.8° (46%),15.7° (16%), 16.1° (10%), 16.4° (80%), 17.9° (17%), 18.2° (19%), 18.7°(96%), 20.0° (38%), 20.3° (100%), 22.6° (11%), 22.8° (76%), 23.2° (50%),24.1° (14%), 24.5° (56%), 24.7° (68%), 25.4° (46%), 25.9° (32%), 26.4°(14%), 26.8° (22%), 27.7° (38%), 28.2° (12%), 29.7° (11%), 29.5° (64%),29.8° (14%), 30.3° (14%), 30.5° (13%) and 32.4° (16%).

It is understood, that the crystalline forms disclosed herein comprisethe COMPOUND in a crystalline form of the free base (i.e. not in form ofa salt). Furthermore, said crystalline forms may comprisenon-coordinated and/or coordinated solvent. Coordinated solvent is usedherein as term for a crystalline solvate. Likewise, non-coordinatedsolvent is used herein as term for physiosorbed or physically entrappedsolvent (definitions according to Polymorphism in the PharmaceuticalIndustry (Ed. R. Hilfiker, VCH, 2006), Chapter 8: U. J. Griesser: TheImportance of Solvates). Crystalline forms A and C are anhydrate oransolvate forms, crystalline form B is a DCM solvate, crystalline form Eis a MeCN solvate and crystalline form K is a DMSO solvate.

FIG. 9 shows the acute effects of ACT-132577 on mean arterial bloodpressure (“MAP”) in conscious, male hypertensive Dahl salt sensitiverats.

FIG. 10 shows the acute effects of ACT-132577 on MAP in conscious, malehypertensive deoxycorticosterone acetate salt rats.

FIG. 11 shows the acute effects of ACT-132577 on MAP in conscious, malespontaneously hypertensive rats.

FIG. 12 shows the acute effects of ACT-132577, used alone or incombination with valsartan, on MAP in conscious, male spontaneouslyhypertensive rats.

FIG. 13 shows the acute effects of ACT-132577, used alone or incombination with valsartan, on MAP in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 14 shows the acute effects of ACT-132577, used alone or incombination with enalapril, on MAP in conscious, male spontaneouslyhypertensive rats.

FIG. 15 shows the acute effects of ACT-132577, used alone or incombination with amlodipine, on MAP in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 16 shows the effects of chronic oral administration of ACT-132577on MAP in conscious, male hypertensive deoxycorticosterone acetate saltrats.

FIG. 17 shows the effects of chronic oral administration of ACT-132577on renal vascular resistance in conscious, male hypertensivedeoxycorticosterone acetate salt rats.

FIG. 18 shows the acute dose-response effect of aprocitentan 1 mg/kg, 3mg/kg, 10 mg/kg, 30 mg/kg) on haematocrit (Hct) 24 hours after a singleoral administration to Wistar rats.

FIG. 19 shows acute effects of EXFORGE HCT® alone, and EXFORGE HCT® incombination with ACT-132577, in male spontaneously hypertensive rats.

FIG. 20 shows acute effects of EXFORGE HCT® alone, and EXFORGE HCT® incombination with spironolactone, in male spontaneously hypertensiverats.

FIG. 21 shows acute effects of EXFORGE HCT® alone, and EXFORGE HCT® incombination with ACT-132577, in male hypertensive deoxycorticosteroneacetate salt rats.

FIG. 22 shows acute effects of EXFORGE HCT® alone, and EXFORGE HCT® incombination with spironolactone, in male hypertensivedeoxycorticosterone acetate salt rats.

DETAILED DESCRIPTION OF THE INVENTION

1) A first embodiment relates to a pharmaceutical compositioncontaining, as active principles, aprocitentan, or a pharmaceuticallyacceptable salt thereof, in combination with an angiotenin receptorblocker which is especially valsartan, or a pharmaceutically acceptablesalt thereof, as well as at least one pharmaceutically acceptableexcipient.2) A second aspect of the present invention relates to a pharmaceuticalcomposition containing, as active principles, aprocitentan, or apharmaceutically acceptable salt thereof, in combination with

-   -   an angiotenin receptor blocker which is especially valsartan, or        a pharmaceutically acceptable salt thereof, and/or    -   a calcium channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof;        as well as at least one pharmaceutically acceptable excipient.        3) A third aspect of the present invention relates to a        pharmaceutical composition containing, as active principles,        aprocitentan, or a pharmaceutically acceptable salt thereof, in        combination with    -   an angiotenin receptor blocker which is especially valsartan, or        a pharmaceutically acceptable salt thereof;    -   a calcium channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof; and    -   a diuretic which is a thiazide-like diuretic (notably        hydrochlorothiazide or chlorthalidone, especially        hydrochlorothiazide), or a pharmaceutically acceptable salt        thereof;        as well as at least one pharmaceutically acceptable excipient.        4) A further embodiment relates to a pharmaceutical composition        according to embodiment 3), wherein the angiotenin receptor        blocker is valsartan or a pharmaceutically acceptable salt        thereof; the calcium channel blocker is amlodipine, or a        pharmaceutically acceptable salt thereof; and the diuretic is        hydrochlorothiazide or a pharmaceutically acceptable salt        thereof, or chlorthalidone or a pharmaceutically acceptable salt        thereof.        5) A further embodiment relates to a pharmaceutical composition        according to embodiment 3) wherein said pharmaceutical        composition comprises aprocitentan or a pharmaceutically        acceptable salt thereof, in combination with valsartan or a        pharmaceutically acceptable salt thereof, and amlodipine, or a        pharmaceutically acceptable salt thereof; and in combination        with hydrochlorothiazide or a pharmaceutically acceptable salt        thereof, or chlorthalidone or a pharmaceutically acceptable salt        thereof; wherein    -   aprocitentan or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 2.5 to 100 mg (in particular 5 or 10 to        50 mg, notably 12.5 mg, 25 mg or 50 mg, especially 12.5 mg or 25        mg) per day of aprocitentan;    -   valsartan or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 100 to 320 mg (in particular 160 or 320        mg, notably 160 mg) per day of valsartan;    -   amlodipine or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 2 to 10 mg (in particular 5 or 10 mg,        notably 5 mg) per day of amlodipine; and    -   hydrochlorothiazide or a pharmaceutically acceptable salt        thereof, if present, is comprised in a pharmaceutical unit        dosage form suitable for the oral administration of 5 to 25 mg        (in particular 12.5 or 25 mg) per day of hydrochlorothiazide;        and chlorthalidone or a pharmaceutically acceptable salt        thereof, if present, is comprised in a pharmaceutical unit        dosage form suitable for the oral administration of 10 to 150 mg        (in particular 15 mg or 30 mg) per day of chlorthalidone.        6) A further embodiment relates to a pharmaceutical composition        according to embodiment 4) wherein the diuretic is        hydrochlorothiazide.        7) A further embodiment relates to a pharmaceutical composition        according to embodiment 6) wherein    -   aprocitentan or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 2.5 to 100 mg (in particular 5 or 10 to        50 mg, notably 12.5 mg, 25 mg or 50 mg, especially 12.5 mg or 25        mg) per day of aprocitentan;    -   valsartan or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 100 to 320 mg (in particular 160 or 320        mg, notably 160 mg) per day of valsartan;    -   amlodipine or a pharmaceutically acceptable salt thereof is        comprised in a pharmaceutical unit dosage form suitable for the        oral administration of 2 to 10 mg (in particular 5 or 10 mg,        notably 5 mg) per day of amlodipine; and    -   hydrochlorothiazide or a pharmaceutically acceptable salt        thereof is comprised in a pharmaceutical unit dosage form        suitable for the oral administration of 5 to 25 mg (in        particular 12.5 mg or 25 mg) per day of hydrochlorothiazide.

In a sub-embodiment, aprocitentan is comprised in a pharmaceutical unitdosage form suitable for the oral administration of 12.5 mg or 25 mg perday of aprocitentan; valsartan or a pharmaceutically acceptable saltthereof is comprised in a pharmaceutical unit dosage form suitable forthe oral administration of 160 mg per day of valsartan; amlodipine or apharmaceutically acceptable salt thereof is comprised in apharmaceutical unit dosage form suitable for the oral administration of5 mg or 10 mg per day of amlodipine; and hydrochlorothiazide or apharmaceutically acceptable salt thereof is comprised in apharmaceutical unit dosage form suitable for the oral administration of12.5 mg or 25 mg per day of hydrochlorothiazide; wherein each dosagecombination, i.e. 12.5 mg/160 mg/5 mg/12.5 mg; 12.5 mg/160 mg/10 mg/12.5mg; 12.5 mg/160 mg/5 mg/25 mg; 12.5 mg/160 mg/10 mg/25 mg; 25 mg/160mg/5 mg/12.5 mg; 25 mg/160 mg/10 mg/12.5 mg; 25 mg/160 mg/5 mg/25 mg;and 25 mg/160 mg/10 mg/25 mg is explicitly disclosed.

“Angiotensin Receptor Blocker” or “ARB” in particular means in thepresent application valsartan, losartan, telmisartan, irbesartan,candesartan, olmesartan, azilsartan, or a pharmaceutically acceptablesalt of one of these. A preferred ARB is valsartan or a pharmaceuticallyacceptable salt thereof.

“Calcium Channel Blocker” or “CCB” in particular means in the presentapplication amlodipine, aranidipine, azelnidipine, barnidipine,benidipine, cilnidipine, clevidipine, isradipine, efonidipine,felodipine, lacidipine, lercanidipine, manidipine, nicardipine,nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine,pranidipine, verapamil or diltiazem or a pharmaceutically acceptablesalt of one of these. A preferred CCB is amlodipine or apharmaceutically acceptable salt thereof.

“Diuretic” in particular means in the present application a diuretic ofthe thiazide class (a thiazide-like diuretic) such as especiallychlorthalidone, hydrochlorothiazide, chlorothiazide, indapamide, ormetolazone. Preferred diuretics are chlorthalidone orhydrochlorothiazide; thus one aspect of the present inventions relatesto combinations of aprocitentan, the ARB valsartan, and the CCBamlodipine, with chlorthalidone; another aspect of the present inventionrelates to combinations of aprocitentan, the ARB valsartan, and the CCBamlodipine, with hydrochlorothiazide.

Further disclosed are, in addition, pharmaceutical compositionscontaining, as active principles, aprocitentan, or a pharmaceuticallyacceptable salt thereof, in combination with an Angiotensin ConvertingEnzyme inhibitor which is especially enalapril, or a pharmaceuticallyacceptable salt thereof, as well as at least one pharmaceuticallyacceptable excipient. “Angiotensin Converting Enzyme inhibitor” or “ACEinhibitor” in particular means in the present application captopril,enalapril, ramipril, quinapril, perindopril, lisinopril, imidapril orcilazapril, or a pharmaceutically acceptable salt of one of these. Apreferred ACE inhibitor is enalapril or a pharmaceutically acceptablesalt thereof.

8) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 17.8°, 20.0°, and 23.5°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.9) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°;wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.10) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°,20.0°, 21.5°, 22.8°, 23.2° and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.11) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.8°, 9.9°, 11.7°, 14.5°, 15.4°,15.6°, 16.9°, 17.2°, 17.8°, 18.6°, 19.9°, 20.0°, 21.5°, 21.9°, 22.8°,23.2°, 23.5°, 24.9°, 25.1°, 25.3°, 25.6°, 25.9°, 27.1°, 27.3°, 28.5°,29.0°, 29.4°, 30.1° and 30.6°; wherein said X-ray powder diffractiondiagram is obtained by using combined Cu Kα1 and Kα2 radiation, withoutKα2 stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.12) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.8° (18%), 9.9° (18%), 11.7° (14%),14.5° (10%), 15.4° (14%), 15.6° (29%), 16.9° (19%), 17.2° (16%), 17.8°(100%), 18.6° (50%), 19.9° (54%), 20.0° (67%), 21.5° (24%), 21.9° (10%),22.8° (18%), 23.2° (49%), 23.5° (83%), 24.9° (32%), 25.1° (20%), 25.3°(24%), 25.6° (33%), 25.9° (16%), 27.1° (23%), 27.3° (39%), 28.5° (13%),29.0° (23%), 29.4° (15%), 30.1° (12%) and 30.6° (10%); wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.

The present data show peaks having a relative intensity, as compared tothe most intense peak in the diagram, of the following percentages(relative peak intensities given in parentheses) at the indicated anglesof refraction 2theta (selected peaks from the range 3-33° 2theta withrelative intensity larger then 10% are reported).

13) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A which essentially showsthe X-ray powder diffraction pattern as depicted in FIG. 1 , whereinsaid X-ray powder diffraction diagram is obtained by using combined CuKα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.

In this context the term “essentially” means that at least the majorpeaks of the diagram depicted in said figures, i.e. those having arelative intensity of more than 10%, especially more than 20%, ascompared to the most intense peak in the diagram, have to be present.However, the person skilled in the art of X-ray powder diffraction willrecognize that relative intensities in X-ray powder diffraction diagramsmay be subject to strong intensity variations due to preferredorientation effects.

14) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form A obtainable bycrystallisation of the COMPOUND in an aqueous solution at pH 6.2 to 6.8.

For avoidance of any doubt, whenever one of the above embodiments refersto “peaks in the X-ray powder diffraction diagram at the followingangles of refraction 2θ”, said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and it should be understood that the accuracy of the 2θvalues as provided herein is in the range of +/−0.1-0.2°. Notably, whenspecifying an angle of refraction 2theta (20) for a peak in theinvention embodiments and the claims, the 2θ value given is to beunderstood as an interval from said value minus 0.2° to said value plus0.2° (2θ+/−0.2°); and preferably from said value minus 0.1° to saidvalue plus 0.1° (2θ+/−0.1°).

When defining the presence of peak in e.g. an X-ray powder diffractiondiagram, a common approach is to do this in terms of the S/N ratio(S=signal, N=noise). According to this definition, when stating that apeak has to be present in an X-ray powder diffraction diagram, it isunderstood that the peak in the X-ray powder diffraction diagram isdefined by having an S/N ratio (S=signal, N=noise) of greater than x (xbeing a numerical value greater than 1), usually greater than 2,especially greater than 3.

Unless used regarding temperatures, the term “about” placed before anumerical value “X” refers in the current application to an intervalextending from X minus 10% of X to X plus 10% of X, and preferably to aninterval extending from X minus 5% of X to X plus 5% of X. In theparticular case of temperatures, the term “about” placed before atemperature “Y” refers in the current application to an intervalextending from the temperature Y minus 10° C. to Y plus 10° C.,preferably to an interval extending from Y minus 5° C. to Y plus 5° C.,notably to an interval extending from Y minus 3° C. to Y plus 3° C. Roomtemperature means a temperature of about 25° C. When in the currentapplication the term n equivalent(s) is used wherein n is a number, itis meant and within the scope of the current application that n isreferring to about the number n, preferably n is referring to the exactnumber n.

Whenever the word “between” or “to” is used to describe a numericalrange, it is to be understood that the end points of the indicated rangeare explicitly included in the range. For example: if a temperaturerange is described to be between 40° C. and 80° C. (or 40° C. to 80°C.), this means that the end points 40° C. and 80° C. are included inthe range; or if a variable is defined as being an integer between 1 and4 (or 1 to 4), this means that the variable is the integer 1, 2, 3, or4.

15) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.7°, 15.7°, and 22.0°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.16) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 19.8° and 22.0°;wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.17) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 17.2°, 17.8°,18.8°, 19.8°, 22.0°, 23.6°, and 25.3°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.18) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 7.8°, 9.7°, 15.7°, 17.2°, 17.8°,18.8°, 19.8°, 20.1°, 20.6°, 21.6°, 22.0°, 23.4°, 23.6°, 24.1°, 24.5°,25.1°, 25.3°, 25.7°, 26.8°, 27.1°, 28.5°, 30.8° and 30.8°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.19) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C characterized by thepresence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 7.8° (23%), 9.7° (42%), 15.7° (37%),17.2° (16%), 17.8° (15%), 18.8° (26%), 19.8° (71%), 20.1° (51%), 20.6°(15%), 21.6° (15%), 22.0° (100%), 23.4° (27%), 23.6° (40%), 24.1° (23%),24.5° (16%), 25.1° (13%), 25.3° (39%), 25.7° (28%), 26.8° (19%), 27.1°(16%), 28.5° (31%), 30.8° (13%) and 30.8° (13%); wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.

The present data show peaks having a relative intensity, as compared tothe most intense peak in the diagram, of the following percentages(relative peak intensities given in parentheses) at the indicated anglesof refraction 2theta (selected peaks from the range 3-33° 2theta withrelative intensity larger then 10% are reported).

20) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C which essentially showsthe X-ray powder diffraction pattern as depicted in FIG. 3 , whereinsaid X-ray powder diffraction diagram is obtained by using combined CuKα1 and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.

In this context the term “essentially” means that at least the majorpeaks of the diagram depicted in said figures, i.e. those having arelative intensity of more than 10%, especially more than 20%, ascompared to the most intense peak in the diagram, have to be present.However, the person skilled in the art of X-ray powder diffraction willrecognize that relative intensities in X-ray powder diffraction diagramsmay be subject to strong intensity variations due to preferredorientation effects.

21) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in crystalline Form C obtainable bycrystallisation of the COMPOUND from MeOH, EtOH or propan-2-ol.

22) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 7), said compositioncomprising aprocitentan in amorphous form. Such amorphous form may beobtained by milling form A. For Example, the amorphous form isobtainable by milling in a ball mill (MM200 Retsch Ball Mill, 2 agatebeads), 30 min at 30 Hz at ambient temperature.

The production of the pharmaceutical compositions can be effected in amanner which will be familiar to any person skilled in the art (see forexample Remington, The Science and Practice of Pharmacy, 21st Edition(2005), Part 5, “Pharmaceutical Manufacturing” [published by LippincottWilliams & Wilkins]) by bringing the crystalline forms of the presentinvention, optionally in combination with other therapeutically valuablesubstances, into a galenical administration form together with suitable,non-toxic, inert, pharmaceutically acceptable solid or liquid carriermaterials and, if desired, usual pharmaceutical adjuvants.

23) A further embodiment relates to a solid pharmaceutical composition(in particular in the form of a tablet) according to any one ofembodiments 1) to 22), especially according to any one of embodiments 8)to 14), or according to any one of embodiments 15) to 21), comprising aspharmaceutically acceptable excipient inert microcrystalline cellulose,lactose, hydroxypropylcellulose, croscarmellose sodium and magnesiumstearate.24) Especially, the solid pharmaceutical composition of embodiment 23)will comprise aprocitentan in a total amount from 5 to 25% in weightbased on the total weight of the pharmaceutical composition,microcrystalline cellulose in a total amount from 2θ to 30% in weightbased on the total weight of the pharmaceutical composition, lactose ina total amount from 40 to 65% in weight based on the total weight of thepharmaceutical composition, hydroxypropylcellulose in a total amountfrom 1 to 3% in weight based on the total weight of the pharmaceuticalcomposition, croscarmellose sodium in a total amount from 2 to 8% inweight based on the total weight of the pharmaceutical composition andmagnesium stearate in a total amount from 0.2 to 2% in weight based onthe total weight of the pharmaceutical composition, whereby the totalpercent in weight of the solid pharmaceutical composition will always be100; the aforementioned solid pharmaceutical composition willparticularly be in the form of a tablet.25) A further embodiment of the invention relates to a pharmaceuticalcomposition according to embodiments 23) to 24), wherein saidpharmaceutical composition is in form of a tablet. In a sub-embodiment,the pharmaceutically active ingredients are comprised in granules priorto compression to said tablet.

A tablet according to embodiment 25) can optionally be coated with asuitable protective pellicle. Said protective pellicle will notablyprevent direct contact of the pharmaceutical composition with moisture;it may also ease imprints that may be desired to be used in order todistinguish the pharmaceutical composition from others.

The coating material for making such protective pellicle may include alow water vapour permeability polymer (such as a polyvinyl alcohol (e.g.Aquapolish® white PVA from manufacturer Biogrund) or dimethylaminoethylmethacrylate (e.g. EUDRAGIT® E P0)). The coating material can furtherinclude a plasticizing agent (e.g. propylene glycol, triacetyne, dibutylphthalate or dibutyl sebacate), a surfactant (e.g. sodium laurylsulphate or a polysorbate such as Tween®) and/or a lubricant/glidant(e.g. stearic acid, magnesium or calcium stearate or talc). Moreover,the coating material can also include a pigment (e.g. iron(II) oxide,iron(III) oxide or titanium oxide) to give the tablet a coloured aspect.

26) A further embodiment of the invention relates to a pharmaceuticalcomposition according to any one of embodiments 23) to 24), wherein saidpharmaceutical composition is in form of a capsule. In a sub-embodiment,the pharmaceutically active ingredients are comprised in granules priorto filling into said capsules.

For avoidance of any doubt, the invention further relates to thecrystalline forms of aprocitentan, especially to crystalline form A,disclosed herein wherein such crystalline form is suitable/is used asfinal isolation step of aprocitentan (e.g. in order to meet the purityrequirements of pharmaceutical production), whereas the finalpharmaceutical composition according to embodiments 1 to 26) may or maynot contain said crystalline form (e.g. because the originallycrystalline form of aprocitentan is further transformed during themanufacturing process and/or is dissolved in the pharmaceuticallyacceptable carrier material(s); thus, in the final pharmaceuticalcomposition, aprocitentan may be present in non-crystalline form, inanother crystalline form, or in dissolved form, or the like).

Such combination pharmaceutical compositions according to embodiments 1)to 26) are especially useful for the treatment of endothelin relateddiseases including hypertension, pulmonary hypertension, coronarydiseases, cardiac insufficiency, renal and myocardial ischemia, renalfailure, cerebral ischemia, dementia, migraine, subarachnoidalhemorrhage, Raynaud's syndrome, digital ulcers or portal hypertension aswell as for the treatment or prevention of atherosclerosis, restenosisafter balloon or stent angioplasty, inflammation, stomach and duodenalulcer, cancer, melanoma, prostate cancer, prostatic hypertrophy,erectile dysfunction, hearing loss, amaurosis, chronic bronchitis,asthma, pulmonary fibrosis, gram negative septicemia, shock, sickle cellanemia, glomerulonephritis, renal colic, glaucoma, connective tissuediseases, diabetic complications, complications of vascular or cardiacsurgery or after organ transplantation, complications of cyclosporintreatment, pain or hyperlipidemia.

The combination pharmaceutical compositions according to embodiments 1)to 26) are also useful for the treatment of Chronic Kidney Disease(CKD), especially CKD of stages 1 to 4 as defined by the Kidney DiseaseImproving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage3), and in particular CKD of these stages caused by essentialhypertension.

The pharmaceutical compositions according to embodiments 1) to 26) areespecially useful for the treatment of hypertension related diseasescomprising hypertension including especially difficult totreat/resistant hypertension; pulmonary hypertension; heart failureincluding especially chronic heart failure; reducing the risk ofdeveloping a major cardiovascular event (such as heart failure,myocardial infarction, stroke, or death from cardiovascular causes) inpatients who are at cardiovascular risk (such as patients who havecoronary artery disease and/or patients who have demonstrated clinicalsigns of congestive heart failure); angina pectoris; and diastolicdysfunction; erectile dysfunction; CKD (especially CKD of stages 1 to 4as defined by the Kidney Disease Improving Global Outcomes (KDIGO)Guidelines (and notably CKD of stage 3), and in particular CKD of thesestages caused by/associated with essential hypertension, especiallyresistant hypertension); and diabetes, and diabetes related diseasessuch as diabetic arteriopathy, diabetic nephropathy, diabeticretinopathy, diabetic vasculopathy; and reducing the risk of developinga major cardiovascular event (such as heart failure, myocardialinfarction, stroke, or death from cardiovascular causes) in patients whohave diabetes that is accompanied by at least one other cardiovascularrisk factor (such as hypertension, especially resistant hypertension).

Preferably, the pharmaceutical compositions according to embodiments 1)to 26) are useful for in the treatment of certain endothelin relateddiseases, which may be defined as a disease selected from the groupconsisting of hypertension, pulmonary hypertension, diabeticarteriopathy, heart failure, erectile dysfunction, angina pectoris andCKD (especially CKD of stages 1 to 4 as defined by the Kidney DiseaseImproving Global Outcomes (KDIGO) Guidelines (and notably CKD of stage3), and in particular CKD of these stages caused by essentialhypertension).

Moreover, the pharmaceutical compositions according to embodiments 1) to19) are useful in the treatment of a disease selected from the groupconsisting of essential hypertension, resistant hypertension, pulmonaryhypertension and pulmonary arterial hypertension (and notably in thetreatment of resistant hypertension).

Essential hypertension (also called primary hypertension or idiopathichypertension) is the form of hypertension that by definition has noidentifiable cause. It represents a significant global public healthconcern, contributing to vascular and renal morbidity and tocardiovascular mortality. The diagnosis of essential hypertension ismade when the average of multiple systolic blood pressure measurementson 2 or more subsequent visits is consistently equal to or above acertain threshold value T_(SBP). Individuals with high normal bloodpressure tend to maintain pressures that are above average for thegeneral population and are at greater risk for development of definitehypertension and cardiovascular events than the general population. Thethreshold value T_(SBP) above which treatment is recommended isregularly discussed among clinicians (see e.g. Mancia et al, J.Hypertens. (2013), 31, 1281-1357); accordingly, depending on thepatient's general condition and age, T_(SBP) could be 140 or 130 mm Hg,or another suitable value.

The term “resistant hypertension” [equivalent to the term “difficult totreat hypertension”] in the present invention is defined as bloodpressure that remains above goal in spite of the concurrent use of 3antihypertensive agents of different classes. One of the 3 agents shouldbe a diuretic and all agents should be prescribed at optimal/maximaldose amounts. As defined, resistant hypertension patients includepatients whose blood pressure is controlled with use of more than 3medications. That is, patients whose blood pressure is controlled butrequire 4 or more medications to do so should be considered resistant totreatment (see e.g. Mancia et al, J. Hypertens. (2013), 31, 1281-1357).

27) A fourth aspect of the invention thus relates to aprocitentan, or apharmaceutically acceptable salt thereof, for use in the treatment ofhypertension, pulmonary hypertension, diabetic arteriopathy, heartfailure, erectile dysfunction, angina pectoris and chronic kidneydisease (notably in the treatment of resistant hypertension), whereinaprocitentan is to be administered in combination with an angioteninreceptor blocker which is especially valsartan, or a pharmaceuticallyacceptable salt thereof.28) A further embodiment relates to aprocitentan, or a pharmaceuticallyacceptable salt thereof, for use in the treatment of hypertension,pulmonary hypertension, diabetic arteriopathy, heart failure, erectiledysfunction, angina pectoris and chronic kidney disease (notably in thetreatment of resistant hypertension), wherein aprocitentan is to beadministered in combination with

-   -   an angiotenin receptor blocker which is especially valsartan, or        a pharmaceutically acceptable salt thereof, and    -   a calcium channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof.        29) A further embodiment relates to aprocitentan, or a        pharmaceutically acceptable salt thereof, for use in the        treatment of hypertension, pulmonary hypertension, diabetic        arteriopathy, heart failure, erectile dysfunction, angina        pectoris and chronic kidney disease (notably in the treatment of        resistant hypertension), wherein aprocitentan is to be        administered in combination with    -   an angiotenin receptor blocker which is especially valsartan or        a pharmaceutically acceptable salt thereof,    -   a calcium channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof; and    -   a diuretic which is a thiazide-like diuretic (notably        hydrochlorothiazide or chlorthalidone, especially        hydrochlorothiazide), or a pharmaceutically acceptable salt        thereof.        30) A further embodiment relates to a pharmaceutical composition        according to any one of embodiments 1) to 26) for use in the        treatment of hypertension, pulmonary hypertension, diabetic        arteriopathy, heart failure, erectile dysfunction, angina        pectoris and chronic kidney disease (notably in the treatment of        resistant hypertension).        31) A further embodiment relates to aprocitentan, or a        pharmaceutically acceptable salt thereof, for use in the        treatment of hypertension including resistant hypertension;        heart failure including chronic heart failure; diastolic        dysfunction; CKD including CKD of stage 3 caused by or        associated with essential hypertension; or for the reduction of        the risk of developing a major cardiovascular event in patients        who have diabetes that is accompanied by at least one other        cardiovascular risk factor comprising hypertension, wherein        aprocitentan is to be administered in combination with    -   an angiotenin receptor blocker which is especially valsartan or        a pharmaceutically acceptable salt thereof,    -   a calcium channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof; and    -   a diuretic which is a thiazide-like diuretic (notably        hydrochlorothiazide or chlorthalidone, especially        hydrochlorothiazide), or a pharmaceutically acceptable salt        thereof.        32) A further embodiment relates to aprocitentan, or a        pharmaceutically acceptable salt thereof, for use according to        embodiments 29) or 31), wherein the angiotenin receptor blocker        is valsartan or a pharmaceutically acceptable salt thereof; the        calcium channel blocker is amlodipine, or a pharmaceutically        acceptable salt thereof; and the diuretic is hydrochlorothiazide        or a pharmaceutically acceptable salt thereof, or chlorthalidone        or a pharmaceutically acceptable salt thereof.        33) A further embodiment relates to aprocitentan, or a        pharmaceutically acceptable salt thereof, for use according to        embodiment 32) wherein the diuretic is hydrochlorothiazide.        34) A further embodiment relates to aprocitentan, or a        pharmaceutically acceptable salt thereof, for use according to        embodiments 32) or 33), wherein, mutatis mutandis, the        pharmaceutically active ingredients are to be administered in a        dosage as disclosed in embodiments 5) or 7).        35) Another embodiment relates to aprocitentan or a        pharmaceutically acceptable salt thereof; to be administered in        combination as defined in any one of embodiments 27) to 29),        or 31) to 34); or to a pharmaceutical composition comprising        aprocitentan or a pharmaceutically acceptable salt thereof, as        defined in any one of embodiments 1) to 26); for use in the        treatment of a disorder selected from the group consisting of        chronic kidney disease (CKD), diabetes, diabetic nephropathy,        diabetic retinopathy, diabetic vasculopathy, chronic heart        failure and diastolic dysfunction.        36) One sub-embodiment of embodiment 35) relates to aprocitentan        or a pharmaceutically acceptable salt thereof, for use in the        treatment of CKD, especially CKD of stages 1 to 4 as defined by        the Kidney Disease Improving Global Outcomes (KDIGO) Guidelines        (and notably CKD of stage 3), and in particular CKD of these        stages caused by essential hypertension.        37) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of diabetes (that is, type 1 or type 2        diabetes).        38) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of diabetic nephropathy.        39) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of diabetic retinopathy.        40) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of diabetic vasculopathy.        41) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of chronic heart failure.        42) According to one variant of sub-embodiment 41), the chronic        heart failure of sub-embodiment 47) will be heart failure with        preserved ejection fraction.        43) According to another variant of sub-embodiment 41), the        chronic heart failure of sub-embodiment 47) will be diastolic        heart failure.        44) Another sub-embodiment of embodiment 35) relates to        aprocitentan or a pharmaceutically acceptable salt thereof, for        use in the treatment of diastolic dysfunction.

Accordingly, aprocitentan or a pharmaceutically acceptable salt thereofaccording is for use in combination with said further pharmaceuticallyactive ingredients. The corresponding combined treatment may be effectedsimultaneously, separately, or over a period of time (especiallysimultaneously).

“Simultaneously”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat approximately the same time; wherein it is understood that asimultaneous administration will lead to exposure of the subject to thetwo or more active ingredients and/or treatments at the same time. Whenadministered simultaneously, said two or more active ingredients may beadministered in a fixed dose combination, or in an equivalent non-fixeddose combination (e.g. by using two or more different pharmaceuticalcompositions to be administered by the same route of administration atapproximately the same time), or by a non-fixed dose combination usingtwo or more different routes of administration; wherein saidadministration leads to essentially simultaneous exposure of the subjectto the two or more active ingredients and/or treatments. For example,when used in combination with an ARB and/or CCB, and, if present, with adiuretic, the COMPOUND would possibly be used “simultaneously”.

“Fixed dose combination”, when referring to an administration type,means in the present application that the administration type concernedconsists in the administration of one single pharmaceutical compositioncomprising the two or more active ingredients, such as especially thepharmaceutical compositions of embodiments 1) to 26).

“Separately”, when referring to an administration type, means in thepresent application that the administration type concerned consists inthe administration of two or more active ingredients and/or treatmentsat different points in time; wherein it is understood that a separateadministration will lead to a treatment phase (e.g. at least 1 hour,notably at least 6 hours, especially at least 12 hours) where thesubject is exposed to the two or more active ingredients and/ortreatments at the same time; but a separate administration may also leadto a treatment phase where for a certain period of time (e.g. at least12 hours, especially at least one day) the subject is exposed to onlyone of the two or more active ingredients and/or treatments. Separateadministration especially refers to situations wherein at least one ofthe active ingredients and/or treatments is given with a periodicitysubstantially different from daily (such as once or twice daily)administration (e.g. wherein one active ingredient and/or treatment isgiven e.g. once or twice a day, and another is given e.g. every otherday, or once a week or at even longer distances).

By administration “over a period of time” is meant in the presentapplication the subsequent administration of two or more activeingredients and/or treatments at different times. The term in particularrefers to an administration method according to which the entireadministration of one of the active ingredients and/or treatments iscompleted before the administration of the other/the others begins. Inthis way it is possible to administer one of the active ingredientsand/or treatments for several months before administering the otheractive ingredient(s) and/or treatment(s).

45) A further embodiment relates to a pharmaceutical compositionaccording to any one of embodiments 1) to 26) for use in the treatmentof hypertension including resistant hypertension; heart failureincluding chronic heart failure; diastolic dysfunction; CKD includingCKD of stage 3 caused by or associated with essential hypertension; orfor the reduction of the risk of developing a major cardiovascular eventin patients who have diabetes that is accompanied by at least one othercardiovascular risk factor comprising hypertension.

It is understood that any embodiment relating to aprocitentan, or apharmaceutically acceptable salt thereof, for use in the treatment ofcertain endothelin related diseases, wherein aprocitentan is to beadministered in combination with further active ingredients such as:

-   -   an angiotenin receptor blocker which is especially valsartan or        a pharmaceutically acceptable salt thereof; or    -   an angiotenin receptor blocker which is especially valsartan or        a pharmaceutically acceptable salt thereof; and a calcium        channel blocker which is especially amlodipine, or a        pharmaceutically acceptable salt thereof; or    -   an angiotenin receptor blocker which is especially valsartan or        a pharmaceutically acceptable salt thereof; a calcium channel        blocker which is especially amlodipine, or a pharmaceutically        acceptable salt thereof; and a diuretic which is a thiazide-like        diuretic (notably hydrochlorothiazide or chlorthalidone,        especially hydrochlorothiazide), or a pharmaceutically        acceptable salt thereof;        such embodiment also relates to such further active ingredients        to be administered in combination with aprocitentan, or a        pharmaceutically acceptable salt thereof; to the use of        aprocitentan for the manufacture of a pharmaceutical composition        comprising aprocitentan and said further active ingredients; to        the use of a pharmaceutical composition comprising aprocitentan        and such further active ingredients for the treatment of such        diseases; and to a method of treating said diseases comprising        administering to a subject (preferably a human) in need thereof        an effective amount of aprocitentan to be administered in        combination with said further active ingredients, or comprising        administering to a subject in need thereof an effective amount        of a pharmaceutical composition comprising aprocitentan and said        further active ingredients as disclosed herein.        46) A further embodiment relates to a method for the treatment        of hypertension, pulmonary hypertension, diabetic arteriopathy,        heart failure, erectile dysfunction, angina pectoris and chronic        kidney disease (notably in the treatment of resistant        hypertension);        comprising the administration of a pharmaceutically effective        amount of aprocitentan, or of a pharmaceutically acceptable salt        thereof, to a subject in need thereof, wherein aprocitentan is        administered in combination with    -   a pharmaceutically effective amount of an angiotenin receptor        blocker which is especially valsartan or a pharmaceutically        acceptable salt thereof,    -   a pharmaceutically effective amount of a calcium channel blocker        which is especially amlodipine, or a pharmaceutically acceptable        salt thereof; and    -   a pharmaceutically effective amount of a diuretic which is a        thiazide-like diuretic (notably hydrochlorothiazide or        chlorthalidone, especially hydrochlorothiazide), or a        pharmaceutically acceptable salt thereof.        47) A further embodiment relates to a method for the treatment        of hypertension, pulmonary hypertension, diabetic arteriopathy,        heart failure, erectile dysfunction, angina pectoris and chronic        kidney disease (notably in the treatment of resistant        hypertension); comprising the administration of a pharmaceutical        composition according to any one of embodiments 1) to 26).        48) A further embodiment relates to a method for the treatment        of hypertension including resistant hypertension; heart failure        including chronic heart failure; diastolic dysfunction; CKD        including CKD of stage 3 caused by or associated with essential        hypertension; or for the reduction of the risk of developing a        major cardiovascular event in patients who have diabetes that is        accompanied by at least one other cardiovascular risk factor        comprising hypertension;        comprising the administration of a pharmaceutically effective        amount of aprocitentan, or of a pharmaceutically acceptable salt        thereof, to a subject in need thereof, wherein aprocitentan is        administered in combination with    -   a pharmaceutically effective amount of an angiotenin receptor        blocker which is especially valsartan or a pharmaceutically        acceptable salt thereof,    -   a pharmaceutically effective amount of a calcium channel blocker        which is especially amlodipine, or a pharmaceutically acceptable        salt thereof; and    -   a pharmaceutically effective amount of a diuretic which is a        thiazide-like diuretic (notably hydrochlorothiazide or        chlorthalidone, especially hydrochlorothiazide), or a        pharmaceutically acceptable salt thereof;        49) A further embodiment relates to a method for the treatment        of hypertension including resistant hypertension; heart failure        including chronic heart failure; diastolic dysfunction; CKD        including CKD of stage 3 caused by or associated with essential        hypertension; or for the reduction of the risk of developing a        major cardiovascular event in patients who have diabetes that is        accompanied by at least one other cardiovascular risk factor        comprising hypertension; comprising the administration of a        pharmaceutical composition according to any one of        embodiments 1) to 26).        50) A further embodiment relates to a method according to        embodiments 46) or 48), wherein the angiotenin receptor blocker        is valsartan or a pharmaceutically acceptable salt thereof; the        calcium channel blocker is amlodipine, or a pharmaceutically        acceptable salt thereof; and the diuretic is hydrochlorothiazide        or a pharmaceutically acceptable salt thereof, or chlorthalidone        or a pharmaceutically acceptable salt thereof.        51) A further embodiment relates to a method according to        embodiment 50) wherein the diuretic is hydrochlorothiazide.        52) A further embodiment relates to a method according to        embodiments 50) or 51), wherein, mutatis mutandis, the        pharmaceutically active ingredients are administered in a dosage        as disclosed in embodiments 5) or 7).

Particular embodiments of the invention are described in the followingExamples, which serve to illustrate the invention in more detail withoutlimiting its scope in any way.

Experimental Procedures

Abbreviations

The following abbreviations are used throughout the specification andthe examples:

Ac acetyl

AcOH acetic acid

aq. aqueous

DCM dichloromethane

DMSO dimethylsulfoxide

EtOAc ethyl acetate

eq. equivalent(s)

FTIR Fourier Transform Infrared Spectroscopy or Spectrum

HPLC High Performance Liquid Chromatography

iPrOAc isopropyl acetate

MeOH methanol

MIBK methyl iso-butyl ketone

org. organic

rt room temperature

THF tetrahydrofuran

vol. volume(s)

w/w weight-per-weight ratio

wt. weight unit

XRPD X-ray powder diffraction

EXAMPLES

Method for Obtaining XRPD Patterns

All XRPD patterns for the solid forms described herein have beenobtained as described hereafter. X-ray powder diffraction patterns werecollected on a Bruker D8 Advance X-ray diffractometer equipped with aLynxeye detector operated with CuKα-radiation in reflection mode(coupled two Theta/Theta). Typically, the X-ray tube was run at of 40kV/40 mA. A step size of 0.02° (2θ) and a step time of 76.8 sec over ascanning range of 3-50° in 2θ were applied. The divergence slit was setto fixed 0.3. Powders were slightly pressed into a silicon singlecrystal sample holder with depth of 0.5 mm and samples were rotated intheir own plane during the measurement. Diffraction data are reportedusing combined Cu Kα1 and Kα2 radiation, without Kα2 stripping. Theaccuracy of the 2θ values as provided herein is in the range of+/−0.1-0.2° as it is generally the case for conventionally recordedX-ray powder diffraction patterns.

Example 1: Form A

1.1. A 3 L double jacketed reactor was charged with5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6fluoropyrimidine (100 g, 0.213 mol, 1 eq.), sulfamide (40.9 g, 0.425mol, 2.0 eq.), K₂CO₃ (147 g, 1.06 mol, 5 eq.) and DMSO (500 mL, 5 vol.)doped with water (2 mL, 0.111 mol, 0.5 eq.). The heterogeneous mixturewas heated to 70° C. during ca. 3 h, after which time completeconversion was observed. After cooling to 20° C., most of the inorganicsalt freight was removed by filtration. The filter cake was washed withEtOAc/iPrOAc 1:1 (300 mL, 3 vol.). Celite (100 g, 1 wt.) topped with alayer of charcoal (20 g, 0.2 wt.) was preconditioned with EtOAc/iPrOAc1:1 (500 mL, 5 vol.) (filtrate discarded). The reaction mixture wasfiltered over this cake and rinsed with EtOAc/iPrOAc 1:1 (300 mL, 3vol.). Then 1M aq. NaOAc solution (500 mL, 0.5 mol, 2.3 eq, 5 vol.) wasadded while keeping the temperature at 25-35° C. The aq. phase waswashed a second time with EtOAc/iPrOAc 1:1 (500 mL, 5 vol.). To the aq.phase, 1M H₂SO₄ (200 mL, 0.2 mol, 1 eq., 2 vol.) was added during 1 h at25-30° C. Crystallization started at pH 8.5-8.0. The crude product wasfiltered off as XRPD pattern form K (DMSO solvate) or a mixture of formA and form K. It was washed twice with water (2×1000 mL, 2×10 vol.). Thesolid was slurried in water (1000 mL, 10 vol.) at rt for 3 h. The solidwas filtered off and slurried a second time in water (1000 mL, 10 vol.)at rt for 3 h. After washing with water (1000 mL, 10 vol.), the pureproduct was dried in vacuum at 40° C. to afford{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideas a white to off-white solid (75 g, 65% yield, XRPD pattern form A).1.2. A reactor (200 L Hastelloy) was charged with5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6fluoropyrimidine (24.2 kg, 51.5 mol), sulfamide (9.7 kg, 100.9 mol, 1.96eq.), potassium carbonate (35.5 kg, 256.9 mol, 5.0 eq.), DMSO (133 kg, 5vol.) and water (490 g, 27.2 mol, 0.53 eq.). The contents of the reactorwere heated to 70-75° C. Monitoring by HPLC showed complete conversionin 4 hours. The contents were cooled to 20-25° C. and the solids werecentrifuged off. Each load was washed with EtOAc/iPrOAc 1:1 (65 kg, 3vol.). The filtrate was re-charged in the reactor and charcoal (2.4 kg,10% w/w) and Celite® (4.8 kg, 20% w/w) were added. The contents wereagitated for 1 h at 15-20° C. and filtered through a cartridge filterback into the reactor. The filters were rinsed with EtOAc/iPrOAc 1:1 (43kg, 2 vol.). NaOAc (8% in water) (124 kg, 5 vol.) was added over 2 h,keeping the temperature below 25° C. After phase separation, the aq.layer was washed with EtOAc/iPrOAc 1:1 (109 kg, 5 vol.) at 20-25° C.Sulfuric acid (5% in water; 64 L, 32.6 mol, 0.63 eq.) was added to theaq. layer at 25-30° C. over 2 hours to reach pH 6.4. The contents werethen cooled to 15-20° C. for 1 h. The solids were filtered off andwashed twice with water (2×24 L, 2×1 vol.). The solid was slurried twicein water (2×242 kg, 2×10 vol.) at 15-20° C. for 3 hours each, filteredand dried, to yield5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideas a white solid (21.6 g, 77% yield, XRPD pattern Form A).

Example 2: Form B (DCM Solvate of the Compound)

5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6fluoropyrimidine (10.0 g, 21.3 mmol, 1.00 eq.), sulfamide (4.1 g, 42.5mmol, 2.0 eq.) and K₂CO₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended inDMSO (50 mL, 5 vol.) and heated to 70° C. for 5 h. The mixture wascooled to rt and EtOAc (40 mL, 4 vol.) followed by water (100 mL, 10vol.) were added. After separation of the layers (org. phase discarded),the aq. phase was extracted with DCM (100 mL, 10 vol.). The DCM layerwas acidified from pH 11.5 to pH 7.0 with conc. AcOH (3 mL, 52 mmol, 2.5eq.), resulting in crystallization of the product. The suspension wascooled to 0° C. for 1 h, then to −5° C. for 15 min. The solid wasfiltered, washed with cold DCM (10 mL, 1 vol.) and dried to yield a DCMsolvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form B as a white solid (9.8 g, 84% yield).

Example 3: Form C

0.2 mL of a stock solution of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidedissolved in THF at 50 mg/mL was dispensed to 3 vials. The solvent wasevaporated for 90 min in a Combidancer device from Hettich AG (Bach,Switzerland) operated at 35° C. and 200 mbar. Immediately thereafter0.015 mL of MeOH for the first vial, EtOH for the second vial and iPrOHfor the third vial was added and the vials were allowed to stand closedfor 3 days. Solid residue of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form C was obtained for each of these solvents.

Example 4: Form D

4.1. A reactor was charged with sulfamide (2.00 eq.), K₂CO₃ (5.00 eq.),5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine(1.00 eq.), DMSO (5.0 vol.) and water (0.02 vol.). The mixture washeated to 75° C. for 2 h. After cooling to 23° C., the suspension wasfiltered and rinsed with EtOAc/iPrOAc 1:1 (5.5 vol.) through thereactor. The filtrate was again filtered through an in-line filter andrinsed with EtOAc/iPrOAc 1:1 (1.5 vol.). A solution of 1M NaOAc in water(5.0 vol.) was added at 27° C., and the layers were separated. The aq.phase was washed with EtOAc/iPrOAc 1:1 (5.0 vol.). The aq. phase wasacidified to pH 5.8 using 0.5M H₂SO₄ in water (2.35 vol.) over 2.5 h,leading to crystallization. After 1 h stirring at 20° C., the suspensionwas filtered and washed with water (2×10 vol.). The solid was slurriedtwice in water (2×10 vol.) at 20° C. for 3 h each, filtered, washed withwater (10 vol.) and dried to give{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form D.

4.2. 50 mg of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form A was dissolved in 3 mL methyl-ethylketone in a new 7 mL glassvial. After sonication in an ultrasound bath for 1 min, the vial wasallowed to stand open at rt for 3 days. The solid residue was{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form D.

Example 5: Form E (MeCN Solvate of the Compound)

{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form A was heated to reflux in 10 volumes of MeCN. After 10 min itwas allowed to cool down to 20° C. within 1 h (heating bath removed). Itwas filtered off and dried under reduced pressure and 45° C. Solidresidue was a MeCN solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form E.

Example 6: Form J

The DCM solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm B (9.4 g, 17.2 mmol, 1.00 eq.) was dissolved in DMSO (19 mL, 2vol.). The solution was added into H₂O (94 mL, 10 vol.) and stirred atrt for 5 min. The resulting suspension was filtered, washed twice withH₂O (2×94 mL, 2×10 vol.) and dried to provide{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm J as a white solid (6.8 g, 72% yield).

Example 7: Form K (DMSO Solvate of the Compound)

7.1.{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm A (1.00 g, 1.83 mmol, 1.00 eq.) was dissolved in DMSO (2 mL, 2vol.). To this solution, 10% H₂O in DMSO (10 mL, 10 vol.) was addedslowly, followed by pure H₂O (2 mL, 2 vol.). Seeding with form Ktriggered crystallization of the product. The suspension was filtered,washed with H₂O (5×10 mL, 5×10 vol.) and dried to give a DMSO solvate{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form K as a white solid (0.95 g, 95% yield).7.2.5-(4-bromophenyl)-4-(2-((5-bromopyrimidin-2-yl)oxy)ethoxy)-6-fluoropyrimidine(10.0 g, 21.3 mmol, 1.00 eq.), sulfamide (4.1 g, 42.5 mmol, 2.0 eq.) andK₂CO₃ (14.7 g, 106 mmol, 5.0 eq.) were suspended in DMSO (50 mL, 5 vol.)and heated to 50° C. for 2θ h. The mixture was cooled to rt and MIBK(100 mL, 10 vol.) followed by water (100 mL, 10 vol.) were added. Afterseparation of the layers (org. phase discarded), the aq. phase wasacidified from pH 11.4 to pH 6.5 with conc. AcOH (4 mL, 70 mmol, 3.3eq.), resulting in crystallization of the product. The solid wasfiltered, washed with water (4×50 mL, 4×5 vol.) and dried to afford aDMSO solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form K as a beige solid (10.4 g, 90% yield).

Example 8: Form L (EtOH Solvate of the Compound)

The DMSO solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamideForm K (100 mg, 0.183 mmol, 1.00 eq.) was slurried in EtOH (0.5 mL, 5vol.) at rt for 4 h. The suspension was filtered, washed twice with H₂O(2×0.5 mL, 2×5 vol.) and dried to afford an EtOH solvate of{5-(4-bromo-phenyl)-6-[2-(5-bromo-pyrimidin-2-yloxy)-ethoxy]-pyrimidin-4-yl}-sulfamidein Form L as a white solid (40 mg, 40% yield).

Example 9: ACT-132577 Tablets

Tablets containing each 50 mg of ACT-132577 can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (250 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight%/tablet Intra- ACT-132577 (amorphous, solid 50.00 20.00 granular form Aor solid form C, as described herein) Microcrystalline cellulose 61.5024.60 Lactose (200M) 122.25 48.90 Hydroxypropylcellulose 5.50 2.20Croscarmellose sodium 4.50 1.80 Water qs qs Extra- Croscarmellose sodium5.00 2.00 granular Magnesium stearate 1.25 0.50 Total 250.00 100.00 qs =quantity sufficient Preferably, ACT-132577 Form A (as described herein)will be used for making the tablets.

Example 10: ACT-132577 Tablets

The tablets of Example 9 can be coated with a layer of Aquapolish® whiteMS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 11: ACT-132577 Tablets

Tablets containing each 50 mg of ACT-132577 can be prepared using a wetgranulation process. The tablet composition is the following:

ACT-132577 tablets (250 mg) MATERIAL (CHEMICAL NAME) mg/tablet Weight%/tablet Intra- ACT-132577 (amorphous, solid 50.00 20.00 granular form Aor solid form C, as described herein) Microcrystalline cellulose 61.2524.50 Lactose (200M) 122.50 49.00 Hydroxypropylcellulose 5.00 2.00Croscarmellose sodium 5.00 2.00 Water qs qs Extra- Croscarmellose sodium5.00 2.00 granular Magnesium stearate 1.25 0.50 Total 250.00 100.00 qs =quantity sufficient Preferably, ACT-132577 Form A (as described herein)will be used for making the tablets.

Example 12

The tablets of Example 11 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 13: ACT-132577 Tablets

Tablets containing each 12.5 mg of ACT-132577 can be prepared using awet granulation process. The tablet composition is the following:

ACT-132577 tablets (100 mg) Material (Chemical name) mg/tablet Weight%/tablet Intra- ACT-132577 (amorphous, solid 12.50 12.50 granular form Aor solid form C, as described herein) Microcrystalline cellulose 27.0027.00 Lactose (200M) 54.00 54.00 Hydroxypropylcellulose 2.00 2.00Croscarmellose sodium 2.00 2.00 Water qs qs Extra- Croscarmellose sodium2.00 2.00 granular Magnesium stearate 0.50 0.50 Total 100.00 100.00 qs =quantity sufficient Preferably, ACT-132577 Form A (as described herein)will be used for making the tablets.

Example 14: ACT-132577 Tablets

The tablets of Example 13 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Example 15: ACT-132577 Tablets

Tablets containing each 12.5 mg of ACT-132577 can be prepared using awet granulation process. The tablet composition is the following:

ACT-132577 tablets (100 mg) MATERIAL mg/ Weight %/ (CHEMICAL NAME)tablet tablet Intra- ACT-132577 (amorphous, solid 12.50 12.50 granularform A or solid form C, as described herein) Microcrystalline cellulose27.50 27.50 Lactose (200M) 53.50 53.50 Hydroxypropylcellulose 2.20 2.20Croscarmellose sodium 1.80 1.80 Water qs qs Extra- Croscarmellose sodium2.00 2.00 granular Magnesium stearate 0.50 0.50 Total 100.00 100.00 qs =quantity sufficient Preferably, ACT-132577 Form A (as described herein)will be used for making the tablets.

Example 16: ACT-132577 Tablets

The tablets of Example 15 can be coated with a layer of Aquapolish®white MS or Aquapolish® white PVA (coating manufacturer: Biogrund).

Properties of the Crystal Forms

Example 17: Storage at Room Temperature

A sample of Form A crystals of the COMPOUND (as obtained according toExample 1 above) has been stored at a temperature of 20-25° C. at 92%relative humidity for 2 months. X-ray powder diffraction performed onthat sample at the end of the 2 months showed that the sample was stillconsisting only in Form A crystals of the COMPOUND. The same result wasobtained after storage for 8 weeks under the above conditions. HPLCcontrol of the sample after 8 weeks storage revealed no significantchange in peak area %, i.e. no significant degradation was observedunder such conditions.

A sample of Form B crystals of a dichloromethane solvate of the COMPOUND(as obtained according to Example 2 above) has been stored in a closedvial (2θ mg of Form B crystals being placed in a closed 4 mL vial) at atemperature of 20-25° C. for about 3 weeks. X-ray powder diffractionperformed on that sample at the end of the 3 weeks showed that the FormB crystals were transformed into Form A crystals of the COMPOUND.

A sample of Form K crystals of a dimethylsulfoxide solvate of theCOMPOUND (as obtained according to Example 7 above) has been stored in aclosed vial (2θ mg of Form K crystals being placed in a closed 4 mLvial) at a temperature of 20-25° C. for about 3 weeks. X-ray powderdiffraction performed on that sample at the end of the 3 weeks showedthat the Form K crystals were transformed into Form A crystals of theCOMPOUND.

Example 18: Hygroscopicity

Form A is considered to be slightly hygroscopic as determined bygravimetric vapor sorption (GVS). Mass increase of a sample as obtainedaccording to Example 1 in the first cycle from 40% r.h. to 80% r.h.corresponds to 0.4%. At 95% r.h. 2.2% moisture were taken up in areversible way without hysteresis upon drying.

Examples of Therapeutic Uses of ACT-132577 Example A: Acute Effects ofACT-132577 in Dahl Salt-Sensitive Rats

The acute effects of ACT-132577 on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malehypertensive Dahl salt-sensitive rats (hereafter “Dahl-S rats”—seedetails about this model in Rapp, Hypertension (1982), 4, 753-763).

Elevated blood pressure is induced in Dahl-S rats by providing 1% sodiumchloride in drinking water. Groups of 6-7 Dahl-S rats were used for thevehicle (7.5% gelatin aqeuous solution) and each dose of ACT-132577tested (0.3, 1, 3, 10, 30, 100, and 300 mg/kg). Effects of ACT-132577 onHR and MAP were calculated for individual animals relative to the 24 hperiod before administering. The results obtained regarding MAP (maximalMAP decrease observed over 6 consecutive hours) are summarised in FIG. 9(data are presented as mean±standard error of the mean). In summary, adose of 10 mg/kg ACT-132577 decreased MAP by 19±4 mm Hg in Dahl-S rats.In contrast to MAP, HR was not affected.

Example B: Acute Effects of ACT-132577 in Deoxycorticosterone AcetateSalt Rats

The acute effects of ACT-132577 on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malehypertensive deoxycorticosterone acetate salt rats (hereafter “DOCA-saltrats”—see details about this model in Gavras et al., Circ. Res. (1975),36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water.Groups of 6-11 DOCA-salt rats were used for the vehicle (7.5% gelatinaquous solution) and each dose of ACT-132577 tested (0.3, 1, 3, 10, 30,100, and 300 mg/kg). Effects of ACT-132577 on HR and MAP were calculatedfor individual animals relative to the 24 h period before administering.The results obtained regarding MAP (maximal MAP decrease observed over 6consecutive hours) are summarised in FIG. 10 (data are presented asmean±standard error of the mean). In summary, a dose of 10 mg/kgACT-132577 decreased MAP by 29±6 mm Hg in DOCA-salt rats. In contrast toMAP, HR was not affected.

Example C: Acute Effects of ACT-132577 in Spontaneaously HypertensiveRats

The acute effects of ACT-132577 on blood pressure, in particular on meanarterial blood pressure (hereafter “MAP”), and heart rate (hereafter“HR”) were evaluated by means of telemetry in conscious, malespontaneously hypertensive rats (hereafter “SHRs”—see details about thismodel in Atanur et al., Genome Res. (2010), 20, 791-803).

Groups of 4-6 SHRs were used for the vehicle (7.5% gelatin aquoussolution) and each dose of ACT-132577 tested (1, 3, 10, 30, 100, and 300mg/kg). Effects of ACT-132577 on HR and MAP were calculated forindividual animals relative to the 24 h period before administering. Theresults obtained regarding MAP (maximal MAP decrease observed over 6consecutive hours) are summarised in FIG. 11 (data are presented asmean±standard error of the mean). In summary, a dose of 100 mg/kgACT-132577 decreased MAP by 18±4 mm Hg in SHRs. In contrast to MAP, HRwas not affected.

Example D: Acute Effects of ACT-132577, Alone or in Combination withValsartan, in Spontaneaously Hypertensive Rats

The acute effects of ACT-132577 administered orally at a single dose of100 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withACT-132577 being used either alone or in combination with valsartanadministered orally at a single dose of 10 mg/kg, were evaluated bymeans of telemetry in conscious, male spontaneously hypertensive rats(hereafter “SHRs”—see details about this model in Atanur et al., GenomeRes. (2010), 20, 791-803).

6 SHRs per treatment group were used for this test. The results obtainedregarding MAP are summarised in FIG. 12 wherein each data point ispresented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(7.5% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of ACT-132577 and valsartan decreased MAPbeyond the predicted (calculated) values, demonstrating synergismbetween the two molecules. In contrast to MAP, HR was not affected inany of the treatment groups.

Example E: Acute Effects of ACT-132577, Alone or in Combination withValsartan, in Deoxycorticosterone Acetate Salt Rats

The acute effects of ACT-132577 administered orally at a single dose of10 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withACT-132577 being used either alone or in combination with valsartanadministered orally at a single dose of 30 mg/kg, were evaluated bymeans of telemetry in conscious, male hypertensive deoxycorticosteroneacetate salt rats (hereafter “DOCA-salt rats”—see details about thismodel in Gavras et al., Circ. Res. (1975), 36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water. 7-8DOCA-salt rats per treatment group were used for this test. The resultsobtained regarding MAP are summarised in FIG. 13 wherein each data pointis presented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of ACT-132577 and valsartan decreased MAPbeyond the predicted (calculated) values, demonstrating synergismbetween the two molecules. In contrast to MAP, HR was not affected inany of the treatment groups.

Example F: Acute Effects of ACT-132577, Alone or in Combination withEnalapril, in Spontaneaously Hypertensive Rats

The acute effects of ACT-132577 administered orally at a single dose of100 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withACT-132577 being used either alone or in combination with enalapriladministered orally at a single dose of 3 mg/kg, were evaluated by meansof telemetry in conscious, male spontaneously hypertensive rats(hereafter “SHRs”—see details about this model in Atanur et al., GenomeRes. (2010), 20, 791-803).

7 SHRs per treatment group were used for this test. The results obtainedregarding MAP are summarised in FIG. 14 wherein each data point ispresented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of ACT-132577 and enalapril decreased MAPbeyond the predicted (calculated) values, demonstrating synergismbetween the two molecules. In contrast to MAP, HR was not affected inany of the treatment groups.

Example G: Acute Effects of ACT-132577, Alone or in Combination withAmlodipine, in Deoxycorticosterone Acetate Salt Rats

The acute effects of ACT-132577 administered orally at a single dose of10 mg/kg on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”), withACT-132577 being used either alone or in combination with amlodipineadministered orally at a single dose of 1 mg/kg, were evaluated by meansof telemetry in conscious, male hypertensive deoxycorticosterone acetatesalt rats (hereafter “DOCA-salt rats”—see details about this model inGavras et al., Circ. Res. (1975), 36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water. 6-8DOCA-salt rats per treatment group were used for this test. The resultsobtained regarding MAP are summarised in FIG. 15 wherein each data pointis presented as a 6-hour mean (NB: the expected additive effect of thecombination of the two drugs, referred to as “Predicted additiveeffect”, was calculated by adding the decreases in blood pressure valuesobtained after administration of each compound separately); the vehicle(4% gelatin aquous solution) treatment had no effect on MAP or HR andthe results obtained are therefore not represented in the figure. Inbrief, co-administration of ACT-132577 and amlodipine decreased MAPbeyond the predicted (calculated) values, demonstrating synergismbetween the two molecules. In contrast to MAP, HR was not affected inany of the treatment groups.

Example H: Chronic Effects of ACT-132577 in Deoxycorticosterone AcetateSalt Rats

The chronic effects of repeated administrations of doses of 1, 10 and100 mg/kg/day of ACT-132577, in particular mean arterial blood pressure(hereafter “MAP”), and heart rate (hereafter “HR”), were evaluated inconscious, male hypertensive deoxycorticosterone acetate salt rats(hereafter “DOCA-salt rats”—see details about this model in Gavras etal., Circ. Res. (1975), 36, 300-309). In the DOCA-salt rats,hypertension is induced by the combination of unilateral nephrectomy,implantation of pellets of the mineralocorticoid analog DOCA, andprovision of 1% sodium chloride in drinking water. The results of theDOCA-salt rats treated with ACT-132577 were compared to those obtainedfor Wistar rats or for DOCA-salt rats that received only the vehicle (4%gelatin aquous solution).

a) The results obtained regarding MAP are summarised in FIG. 16 whereineach data point is presented as a 24-hour mean. 6 rats were used foreach of the 5 test groups (Wistar control rats (bottom line in FIG. 16), DOCA-salt control rats (top line in FIG. 16 ) and DOCA-salt ratsreceiving repeated administrations of doses of 1, 10 and 100 mg/kg/dayof ACT-132577 (second to third line from top, respectively, in FIG. 16)). In brief, oral administration of ACT-132577 for 4 weeksdose-dependently attenuated the DOCA-salt-induced increase in MAPwithout changing HR.b) The results obtained regarding renal vascular resistance aresummarised in FIG. 17 wherein:

-   -   DOCA Ø 2 w represents DOCA-salt rats sacrified just before        initiation of treatment with ACT-132577; and    -   the “*” symbol in represents a statistical significance factor        p<0.05 when using a one way ANOVA followed by a Newmal-Keuls        multiple comparisons post-hoc test.

In summary, based on these tests, chronic oral administration ofACT-132577 to DOCA-salt rats dose-dependently increased renal blood flowand decreased renal vascular resistance. ACT-132577 also tended todecrease left ventricular hypertrophy, as suggested by thedose-dependent decrease in plasma concentrations of N-terminal pro-brainnatriuretic peptide (NTproBNP).

Example I: Effects of ACT-132577, Alone or in Combination with an ACEInhibitor or an ARB, in Animal Models of Diabetes

The effects of ACT-132577 can be assessed in diabetic rodent models (inthis regard, see the models described in the following references: Senet al, Life Sci. (2012), 91(13-14), 658-668; Janiak et al., Eur. J.Pharmacol. (2006), 534, 271-279; and Iglarz et al, J. Pharmacol. Exp.Ther. (2008), 327(3), 736-745). In particular, the effect of ACT-132577,alone or in combination, on glucose tolerance, insulinemia and end organdamage can be investigated. End organ damage includes: vascularfunction, renal function (e.g. proteinuria), cardiac function andremodelling and any other target organ affected by diabetes (e.g. theeye).

Example J: Evaluation of the Effect of ACT-132577 on Fluid Retention

A decrease in haematocrit (Hct) or haemoglobin occurs secondary to anincrease in plasma volume and can be used as a marker of fluidretention. A single oral dose of aprocitentan (1-30 mg/kg) or vehicle(gelatin) was administered by gavage to male Wistar rats. Twenty-fourhours after administration, sublingual blood was sampled underisoflurane-induced anesthesia. Haematocrit was measured using ahematology analyser. ACT-132577 did not impact on haematocrit (Hct)suggesting low liability on fluid retention (FIG. 18 ).

Comparison Example 1: Acute Effects of Spironolactone Used inCombination with Valsartan in Spontaneaously Hypertensive Rats

The acute effects of spironolactone (300 mg/kg) on blood pressure, inparticular on mean arterial blood pressure (hereafter “MAP”), and heartrate (hereafter “HR”) in combination with valsartan, each administeredorally as single doses, were also evaluated by means of telemetry inconscious, male spontaneously hypertensive rats (hereafter “SHRs”—seedetails about this model in Atanur et al., Genome Res. (2010), 20,791-803) using a protocol analog to that described in Example D.

Unlike for ACT-132577, no synergistic effect was seen on MAP reductionfor the combination of spironolactone treatment with valsartantreatment.

Comparison Example 2: Acute Effects of Spironolactone Used inCombination with Valsartan in Deoxycorticosterone Acetate Salt Rats

The acute effects of spironolactone (300 mg/kg) on blood pressure, inparticular on mean arterial blood pressure (hereafter “MAP”), and heartrate (hereafter “HR”) in combination with valsartan, each administeredorally as single doses, were also evaluated by means of telemetry inconscious, male hypertensive deoxycorticosterone acetate salt rats(hereafter “DOCA-salt rats”—see details about this model in Gavras etal., Circ. Res. (1975), 36, 300-309) using a protocol analog to thatdescribed in Example E.

Unlike for ACT-132577, no synergistic effect was seen on MAP reductionfor the combination of spironolactone treatment with valsartantreatment.

Comparison Example 3: Acute Effects of Spironolactone Used inCombination with Enalapril in Spontaneaously Hypertensive Rats

The acute effects of spironolactone (300 mg/kg) on blood pressure, inparticular on mean arterial blood pressure (hereafter “MAP”), and heartrate (hereafter “HR”) in combination with valsartan, each administeredorally as single doses, were also evaluated by means of telemetry inconscious, male spontaneously hypertensive rats (hereafter “SHRs”—seedetails about this model in Atanur et al., Genome Res. (2010), 20,791-803) using a protocol analog to that described in Example F.

Unlike for ACT-132577, no synergistic effect was seen on MAP reductionfor the combination of spironolactone treatment with enalapriltreatment.

Example K: Acute Effects of EXFORGE HCT® Alone, and EXFORGE HCT® inCombination with ACT-132577 or Spironolactone, in SpontaneouslyHypertensive Rats

The acute effects of Exforge HCT® (i.e. a fixed dose combination ofvalsartan/amlodipine/hydrochlorothiazide; dosage adapted for 1.6mg/kg/0.1 mg/kg/0.25 mg/kg for valsartan/amlodipine/hydrochlorothiazide,respectively) on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”) incombination with ACT-132577 or spironolactone were also evaluated bymeans of telemetry in conscious, male spontaneously hypertensive rats(hereafter “SHRs”-see details about this model in Atanur et al., GenomeRes. (2010), 20, 791-803).

9 SHRs per treatment group were used for this test. To match the maximaleffect on blood pressure of co-administered drug in this model,aprocitentan 100 mg/kg was administrated orally on the 3^(rd) dayfollowing 3-day oral administration of Exforge HCT® mg/kg andspironolactone 300 mg/kg was co-administered orally with Exforge HCT® onthe 1^(st) day followed by 2 days of Exforge HCT® administration. Theresults obtained regarding MAP are summarised in FIGS. 19 and 20 whereineach data point is presented as a 6-hour mean.

When added on top of Exforge HCT®, aprocitentan or spironolactonefurther reduced blood pressure. However, aprocitentan induced a greaterblood pressure reduction than spironolactone. In contrast to MAP, HR wasnot affected in any of the treatment groups.

Example L: Acute Effects of EXFORGE HCT® Alone, and EXFORGE HCT® inCombination with ACT-132577 or Spironolactone, in DeoxycorticosteroneAcetate Salt Rats

The acute effects of Exforge HCT® (dosage adapted for 3.2 mg/kg/0.2mg/kg/0.5 mg/kg for valsartan/amlodipine/hydrochlorothiazide,respectively) on blood pressure, in particular on mean arterial bloodpressure (hereafter “MAP”), and heart rate (hereafter “HR”) incombination with ACT-132577 (10 mg/kg) or spironolactone (300 mg/kg),each administered orally as single doses, were also evaluated by meansof telemetry in conscious, male hypertensive deoxycorticosterone acetatesalt rats (hereafter “DOCA-salt rats”-see details about this model inGavras et al., Circ. Res. (1975), 36, 300-309).

In the DOCA-salt rats, hypertension is induced by the combination ofunilateral nephrectomy, implantation of pellets of the mineralocorticoidanalog DOCA, and provision of 1% sodium chloride in drinking water. 7-9DOCA-salt rats per treatment group were used for this test. The resultsobtained regarding MAP are summarised in FIGS. 21 and 22 wherein eachdata point is presented as a 6-hour mean.

When added on top of Exforge HCT®, aprocitentan 10 mg/kg orspironolactone 300 mg/kg further reduced blood pressure. However,aprocitentan induced a greater blood pressure reduction thanspironolactone. In contrast to MAP, HR was not affected in any of thetreatment groups.

The invention claimed is:
 1. A pharmaceutical composition containing, asactive principles, aprocitentan, or a pharmaceutically acceptable saltthereof, in combination with: an angiotensin converting enzymeinhibitor, or a pharmaceutically acceptable salt thereof; as well as atleast one pharmaceutically acceptable excipient; wherein saidcomposition comprises aprocitentan in crystalline Form A characterizedby the presence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 17.8°, 20.0°, and 23.5°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1andKα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.
 2. The pharmaceutical compositionaccording to claim 1, wherein said angiotensin converting enzymeinhibitor is enalapril, or a pharmaceutically acceptable salt thereof.3. The pharmaceutical composition according to claim 2, wherein saidaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 4. The pharmaceutical composition accordingto claim 2, wherein said aprocitentan in crystalline Form A essentiallyshows the X-ray powder diffraction pattern as depicted in FIG. 1 ,wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.
 5. A method forthe treatment of hypertension; heart failure; diastolic dysfunction; orchronic kidney disease (CKD); or for the reduction of the risk ofdeveloping a major cardiovascular event in patients who have diabetesthat is accompanied by at least one other cardiovascular risk factorcomprising hypertension; comprising the administration of apharmaceutically effective amount of aprocitentan, or of apharmaceutically acceptable salt thereof, to a subject in need thereof,wherein aprocitentan is administered in combination with apharmaceutically effective amount of an angiotensin converting enzymeinhibitor or a pharmaceutically acceptable salt thereof; and wherein theaprocitentan is in crystalline Form A characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 17.8°, 20.0°, and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2.
 6. The method according to claim 5, whereinsaid angiotensin converting enzyme inhibitor is enalapril, or apharmaceutically acceptable salt thereof.
 7. The method according toclaim 5, wherein said method is for the treatment of hypertension. 8.The method according to claim 6, wherein said method is for thetreatment of hypertension.
 9. A method for the treatment ofhypertension, heart failure, or chronic kidney disease (CKD); comprisingadministering a pharmaceutically effective amount of aprocitentan, or ofa pharmaceutically acceptable salt thereof, to a subject in needthereof, wherein aprocitentan is administered in combination with apharmaceutically effective amount of an angiotensin converting enzymeinhibitor or a pharmaceutically acceptable salt thereof; and wherein theaprocitentan is in crystalline Form A characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 17.8°, 20.0°, and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2.
 10. The method according to claim 9, whereinsaid angiotensin converting enzyme inhibitor is enalapril, or apharmaceutically acceptable salt thereof.
 11. The method according toclaim 5, wherein the aprocitentan in crystalline Form A is characterizedby the presence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°;wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.
 12. The methodaccording to claim 7, wherein aprocitentan is administered in apharmaceutical unit dosage form suitable for the oral administration of10 to 50 mg per day of aprocitentan.
 13. The method according to claim8, wherein aprocitentan is administered in a pharmaceutical unit dosageform suitable for the oral administration of 10 to 50 mg per day ofaprocitentan.
 14. The method according to claim 9, wherein said methodis for the treatment of chronic kidney disease (CKD).
 15. The methodaccording to claim 14, wherein said method is for the treatment of CKDof stages 1 to 4 caused by or associated with essential hypertension.16. The method according to claim 10, wherein said method is for thetreatment of chronic kidney disease (CKD).
 17. The method according toclaim 16, wherein said method is for the treatment of CKD of stages 1 to4 caused by or associated with essential hypertension.
 18. The methodaccording to claim 14, wherein the aprocitentan in crystalline Form A ischaracterized by the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 19. The method according to claim 16, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 20. The method according to claim 7, whereinsaid hypertension is resistant hypertension.
 21. The method according toclaim 8, wherein said hypertension is resistant hypertension.
 22. Themethod according to claim 11, wherein said method is for the treatmentof chronic heart failure.
 23. The method according to claim 20, whereinaprocitentan is administered in a pharmaceutical unit dosage formsuitable for the oral administration of 10 to 50 mg per day ofaprocitentan.
 24. The method according to claim 21, wherein aprocitentanis administered in a pharmaceutical unit dosage form suitable for theoral administration of 10 to 50 mg per day of aprocitentan.
 25. Themethod according to claim 7, wherein the aprocitentan in crystallineForm A is characterized by the presence of peaks in the X-ray powderdiffraction diagram at the following angles of refraction 2θ: 17.8°,18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powder diffractiondiagram is obtained by using combined Cu Kα1 and Kα2 radiation, withoutKα2 stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 26. The method according to claim 8, wherein the aprocitentanin crystalline Form A is characterized by the presence of peaks in theX-ray powder diffraction diagram at the following angles of refraction2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 27. The method according to claim 9, whereinthe aprocitentan in crystalline Form A is characterized by the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.
 28. The method according to claim15, wherein the aprocitentan in crystalline Form A is characterized bythe presence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°;wherein said X-ray powder diffraction diagram is obtained by usingcombined Cu Kα1 and Kα2 radiation, without Kα2 stripping; and theaccuracy of the 2θ values is in the range of 2θ+/−0.2°.
 29. The methodaccording to claim 17, wherein the aprocitentan in crystalline Form A ischaracterized by the presence of peaks in the X-ray powder diffractiondiagram at the following angles of refraction 2θ: 17.8°, 18.6°, 20.0°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 30. The method according to claim 20, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 31. The method according to claim 21, whereinthe aprocitentan in crystalline Form A is characterized by the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 17.8°, 18.6°, 20.0°, 23.2° and 23.5°; wherein saidX-ray powder diffraction diagram is obtained by using combined Cu Kα1and Kα2 radiation, without Kα2 stripping; and the accuracy of the 2θvalues is in the range of 2θ+/−0.2°.
 32. The method according to claim7, wherein the aprocitentan in crystalline Form A is characterized bythe presence of peaks in the X-ray powder diffraction diagram at thefollowing angles of refraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°,20.0°, 21.5°, 22.8°, 23.2° and 23.5°; wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 33. The method according to claim 8, whereinthe aprocitentan in crystalline Form A is characterized by the presenceof peaks in the X-ray powder diffraction diagram at the following anglesof refraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 34. The method according to claim 14, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 35. The method according to claim 16, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 36. The method according to claim 23, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 20 values is in the range of2θ+/−0.2°.
 37. The method according to claim 24, wherein theaprocitentan in crystalline Form A is characterized by the presence ofpeaks in the X-ray powder diffraction diagram at the following angles ofrefraction 2θ: 9.8°, 9.9°, 11.7°, 17.8°, 18.6°, 20.0°, 21.5°, 22.8°,23.2° and 23.5°; wherein said X-ray powder diffraction diagram isobtained by using combined Cu Kα1 and Kα2 radiation, without Kα2stripping; and the accuracy of the 2θ values is in the range of2θ+/−0.2°.
 38. The method according to claim 16, wherein theaprocitentan in crystalline Form A essentially shows the X-ray powderdiffraction pattern as depicted in FIG. 1 , wherein said X-ray powderdiffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.
 39. The method according to claim 21, whereinthe aprocitentan in crystalline Form A essentially shows the X-raypowder diffraction pattern as depicted in FIG. 1 , wherein said X-raypowder diffraction diagram is obtained by using combined Cu Kα1 and Kα2radiation, without Kα2 stripping; and the accuracy of the 2θ values isin the range of 2θ+/−0.2°.